The aim of this project is to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to evaluate interventions that might alter age-related performance decrements. Rodent and nonhuman primate models are tested in a variety of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include various nutritional, hormonal and pharmacological treatments. Multiple genotypes and genetically modified mice are examined to determine possible genetic involvement in age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rodents using manipulations of the cholinergic and glutamatergic neurotransmitter systems. The lead cholinergic compound in this effort is the cholinesterase inhibitor, phenserine, which is currently in Phase III clinical trials using oral dosing in patients with Alzheimer?s disease (AD). We have also continued work examining the role of nitric oxide in memory dysfunction. Nitric oxide enhances guanylate cyclase and production of the second messenger, cyclic guanosine monophosphate (cGMP), which in turn stimulates glutamate release. Inhibitors of cGMP-specific phosphodiesterase enzyme type 5 (PDE-5) can enhance cGMP activity. Sildenafil citrate, the main ingredient in Viagra, is one such PDE-5 inhibitor in clinical use for erectile dysfunction. In addition, clinical reports of persons using this compound have indicated cognitive effects which have been demonstrated in animal learning experiments. We are evaluating this compound and related compounds on maze performance in rats. We observed that sildenafil can attenuate a maze learning impairment in young rats induced by antagonism of nitric oxide synthase, the enzyme involved in production of nitric oxide. We have now found that treatment of aged rats does not enhance maze learning but does enhance retention. We have also examined the effects of the PDE-4 inhibitor, rolipram, which enhances cAMP activity and has been reported to enhance learning in a variety of tasks. We have found no evidence rolipram improves maze learning; in fact, we have observed impaired learning and reduced locomotor activity following rolipram treatment. We are evaluating other PDE inhibitors to evaluate their cognitive enhancing effects. We also continue to assess the effects of a low calorie diet and various diet regimens on various parameters of brain function as well as pharmaceuticals that mimic the effects of calorie restriction. As an example, we have found that mice fasted every other day show greater resistance to kainic induced seizures compared to mice fed every day. In addition, mice fasted on two days a week also have reduced seizure activity. We are currently completing studies in rats that examine the effects of a high fiber diet (methylcellulose) and well as studies of the susceptibility to neurotoxicity of rats on high fat and protein diets. Studies of neuromorphometric changes in mouse models of Alzheimer?s disease (AD) are also continuing including quantitation of changes in the length and complexity of capillaries and in particular populations of nerve fibers, specifically those containing tyrosine hydroxylase (TH). Using methods of unbiased stereology, we have found that transgenic mice expressing mutations of the amyloid precursor protein (APP) and presenilin-1 genes have markedly reduced numbers of TH containing neurons in the locus coeruleus, a neural locus that regulates many forebrain functions including attention and memory. Regarding other progress for conducting neuromorphometrics using unbiased stereology, we continue progress in developing an automated method for counting neurons that are can be stained in high contrast to their background.